CN101466365A - Method for enhancing cognitive function - Google Patents

Method for enhancing cognitive function Download PDF

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Publication number
CN101466365A
CN101466365A CNA2007800205620A CN200780020562A CN101466365A CN 101466365 A CN101466365 A CN 101466365A CN A2007800205620 A CNA2007800205620 A CN A2007800205620A CN 200780020562 A CN200780020562 A CN 200780020562A CN 101466365 A CN101466365 A CN 101466365A
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quinoline
addition salts
pharmaceutically useful
useful acid
piperazine
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W·D·赫斯特
T·A·科默里
S·阿什米斯
S·J·罗森茨魏希-利普森
L·E·谢克特
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Wyeth LLC
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Wyeth LLC
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Abstract

Pharmaceutical compositions and compositions are provided for treating cognitive disorders using synergistically effective amounts of 5-HT1A receptor antagonists and cognition enhancers.

Description

Strengthen the method for cognitive function
Invention field
[0001] the present invention relates to treat the method for cognitive dysfunction.Specifically, the present invention relates to treat the method for cognitive dysfunction, it comprises uses 5-HT 1ABonding agent, particularly 5-HT 1AThe combination of receptor antagonist and cognitive enhancer, and relate to the 5-HT that comprises with the effective dose of cooperative mode 1AThe pharmaceutical composition of bonding agent and cognitive enhancer.
Background technology
[0002] current to cognitive dysfunction, for example the treatment of the cognitive defect relevant with Alzheimer may have undesirable side effect, for example hepatic injury, gastro-intestinal problems (for example feel sick, diarrhoea and vomiting), food digestion problem, anorexia, stomachache, fatigue and dizzy.Owing to consider the generation or the seriousness of the side effect relevant, do not advise carrying out therapeutic alliance usually with these medicines.And the cognitive effect of the viewed positive of current treatment possibly can't be kept the longer time.Therefore, need to determine effectively to improve or to prevent cognitive dysfunction, for example chemical compound and the therapeutic scheme of the cognitive defect relevant with Alzheimer.Similarly, need determine to have the chemical compound and the therapeutic scheme of lower side effect occurrence risk.
Summary of the invention
[0003] Fig. 1 is the result's of new object identification (NOR) test form signal, and it demonstrates with solvent, single aricept with 0.5mg/kg (0.5), single with 0.3mg/kg 405 and use 405 and
Figure A200780020562D00112
The mice treated of combination between difference aspect inquiry.
[0004] Fig. 2 is the result's of NOR test form signal, and it demonstrates with solvent, single with 0.5mg/kg's
Figure A200780020562D00113
(0.5), single with 0.3mg/kg 405 and use 405 and
Figure A200780020562D00114
The mice treated of combination between in identification with keep difference aspect the memory.
Detailed Description Of The Invention
[0005] having been found that ought be as 5-HT 1AThe chemical compound of receptor antagonist and cognitive enhancer together during administration, have synergism for strengthening cognition.In certain embodiments, 5-HT 1AAgonist compounds and cognitive enhancer are carried out administration to be lower than therapeutic dose separately.Therefore, when with 5-HT 1AWhen antagonist is studied as effective therapy of various diseases of the central nervous system who comprises cognitive dysfunction, thus astonishing and be that two kinds of medicines that play a role by different physiological mechanisms being lower than therapeutic dose play a role with cooperative mode and strengthen cognition unexpectedly.
[0006] therefore, the present invention relates to the method for treatment cognitive disorder in its patient of needs.This method comprises to patient uses 5-HT with the effective dose of cooperative mode 1AAgonist compounds and cognitive enhancer.In one embodiment, the amount of the cognitive enhancer of using to its patient of needs is less than without 5-HT 1ABe used to strengthen cognitive effective dose during antagonist individually dosed.In one embodiment, the 5-HT that uses to its patient of needs 1AThe amount of agonist compounds is used to strengthen cognitive effective dose when being less than without cognitive enhancer individually dosed.
[0007] cognitive disorder or cognitive dysfunction include but not limited to mild cognitive impairment (MCI), dementia, delirium, amnesia, Alzheimer, parkinson disease, Huntington Chorea; Dysmnesia comprise the memory impairment relevant with the dementia of depression, alzheimer disease, Alzheimer; Cognitive defect or the cognitive dysfunction relevant with neurological's situation, described neurological's situation comprises for example parkinson disease (PD), Huntington Chorea (HD), Alzheimer, depression and schizophrenia (and other psychosiss, for example paranoia and Ma Nuo (mano-) depression); Schizoid cognitive dysfunction, attention and learning disorder be attention deficit disorder (for example hyperkinetic syndrome (ADHD)) and reading disorder for example, the cognitive dysfunction relevant with dysplasia be mongolism and fragile X syndrome for example, carry out afunction, learning information forfeiture, vascular dementia, schizophrenia, cognitive decline, neurodegenerative disorders and other dementias, the dementia that for example causes or cause by Different types of etiopathogenises because of HIV disease, head trauma, parkinson disease, Huntington Chorea, Pick's disease, creutzfeldt-Jacob disease.Cognitive relevant disease also includes but not limited to and MCI and dull-witted as relevant cognitive dysfunction dull-witted after Louis corpusculum dementia, vascular dementia and the apoplexy.The present invention also can the treatment cognitive dysfunction relevant with operation technique, traumatic brain injury or apoplexy.
[0008] as 5-HT 1AThe chemical compound of antagonist is and 5-HT 1AThe bonded chemical compound of receptor-selective.More particularly, these chemical compound antagonisms 5-HT 1AThe activity of receptor.Those skilled in the art can use many methods well known in the art easily to identify 5-HT 1AThe chemical compound of antagonist, described method comprise for example pharmacology test method of those standards as herein described.
[0009] term " administration " or " using " are meant direct officinal salt or compositions to animal administered compound or chemical compound as used herein, perhaps to the officinal salt or the compositions of prodrug derivant or the analog or the chemical compound of animal administered compound, they can form the reactive compound of equivalent in animal body.
[0010] term " animal " includes but not limited to people, mice, rat, Cavia porcellus, Canis familiaris L., cat, horse, cattle, pig, monkey, chimpanzee, baboon or macaque as used herein.In one embodiment, described animal is a mammal.In another embodiment, described animal is the people.
[0011] in one embodiment, as 5-HT 1AThe chemical compound of antagonist comprises U.S. Patent number 6,127,357 and 6,465,482, the u.s. patent application serial number of submitting on March 30th, 2,006 11/396,307 that is called " the 5-hydroxy tryptamine energy medicine that is used for the treatment of sexual dysfunction ", " 5-HT by name that submits on June 9th, 2006 1AThe piperazine-piperidine antagonist and the agonist of receptor " u.s. patent application serial number 11/450,942 and the chemical compound described in International Patent Publication No. WO 97/03982 and the WO 95/33743, it all is incorporated herein by reference.These chemical compounds can prepare according to the method described in these patents and the patent publication.In one embodiment, 5-HT 1AAntagonist comprises people such as Caliendo, " as 5-HT 1ADerivant-the past of receptors ligand and present ", CurrentMedicinal Chemistry, the chemical compound described in the 12:1721-1753 (2005), it is incorporated herein by reference.By the described 5-HT of people such as Caliendo 1AThe limiting examples of antagonist comprises amino tetrahydronaphthalene (for example S-UH301 and 5-Me-OH-DPAT), ergoline class, aryl piperazines class (for example chemical compound 114 in the chemical compound 100-106 in SDZ 216,525, DU 125530, DU 125430, the table 1, the chemical compound in the table 2 124,125,127 and 128, the table 3 and the chemical compound 131 and 132 in the table 4), indolyl alkyl amine, aporphine (for example compd A) and aryloxyalkylamines.
Table 1
Figure A200780020562D00142
Table 2
Figure A200780020562D00151
Data are expressed as * IC 50Value.
Table 3
Figure A200780020562D00161
IC 50(nM)
Chemical compound Ar R 5-HT 1A
112 3，4-(-OCH 2O-)-Ph H 20
113 4-OCH 3-Ph H 50
114 3，4-(-OCH 2O-)-Ph 3-OCH 3 2.2
Table 4
Figure A200780020562D00162
Figure A200780020562D00164
Compd A
[0012] non-limiting instance that is used for The compounds of this invention includes but not limited to:
(R)-and 4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide (coming Kao Zuotan) and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide (chemical compound 405) and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline or its pharmaceutically useful acid-addition salts,
5-fluoro-4-methoxyl group-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl)-2-(trifluoromethyl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
8-{4-[4-(1H-indole-4-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-{4-[4-(5-fluoro-benzofuran-3-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
7-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-(4-(1-(quinoline-8-ylmethyl) piperidin-4-yl) piperazine-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-(4-(1-(quinoline-8-ylmethyl) piperidin-4-yl) piperazine-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-5-fluoroform yl-quinoline and pharmaceutically useful acid-addition salts thereof,
5-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-[4-(4-quinoline-8-base-piperazine-1-yl)-piperidines-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof and
8-[4-(4-benzofuran-3-base-piperazine-1-yl)-piperidines-1-yl]-6-chloro-quinoline and pharmaceutically useful acid-addition salts thereof.
[0013] in certain embodiments, 5-HT 1AAgonist compounds is following any one:
(R)-and 4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide (coming Kao Zuotan) and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
[0014] in special embodiment, 5-HT 1AAgonist compounds is
(R)-and 4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide (coming Kao Zuotan) and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof, or
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
[0015] In a more specific embodiment, 5-HT 1AAgonist compounds is
(R)-and 4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide (coming Kao Zuotan) and pharmaceutically useful acid-addition salts thereof, or
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof.
[0016] in the most special embodiment, 5-HT 1AAgonist compounds is
(R)-and 4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide (coming Kao Zuotan) and pharmaceutically useful acid-addition salts thereof.
[0017] pharmaceutically useful salt acid-addition salts normally, it can be by general formula compound as herein described and pharmaceutically useful acid such as benzoic acid, phosphoric acid, sulphuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malic acid, mandelic acid, glactaric acid, nitric acid, fumaric acid, succinic acid, tartaric acid, acetic acid, lactic acid, pounce on acid, pantothenic acid, benzenesulfonic acid, adipic acid or methanesulfonic acid forms.In some embodiments of the present invention, described acid-addition salts is hydrochloric acid or succinate.Can use other officinal salts well known by persons skilled in the art.
[0018] with 5-HT of the present invention 1AThe cognitive enhancer of agonist compounds administering drug combinations includes but not limited to: the medicine (for example, acetylcholinesterase or cholinesterase inhibitor, cholinergic agonist or 5-hydroxytryptamine receptor antagonist) of regulating neurotransmitter levels; The medicine of adjusting solubility A β level, amyloid fibrils formation or amyloid plaque load (for example; inhibitors of gamma-secretase, beta-secretase inhibitor, Antybody therapy and degraded enzyme) and the medicine (for example, antioxidant, inhibitors of kinases, caspase inhibitor and hormone) of neuroprotective unit integrity.Comprise with other representational drug candidates of The compounds of this invention administering drug combinations: cholinesterase inhibitor (for example, tacrine
Figure A200780020562D00191
Donepezil
Figure A200780020562D00192
Sharp this bright
Figure A200780020562D00193
Galantamine
Figure A200780020562D00194
Metrifonate, physostigmine and huperzine A); N-methyl-D-aspartate salt (NMDA) antagonist and agonist are (for example, dextromethorphan, memantine, Zhuo Xiping maleate (MK-801), xenon, remacemide, eliprodil, amantadine, D-cycloserine, felbamate, ifenprodil, CP-101606 (Pfizer), De Luxi is bright and U.S. Patent number 6,821,985 and 6, chemical compound described in 635,270); Ampakine class (for example cyclothiazide, aniracetam, CX-516
Figure A200780020562D00195
CX-717, CX-516, CX-614 and CX-691 (Cortex drugmaker, Irvine, CA), 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S, the S-dioxide is (referring to people such as Zivkovic, 1995, J.Pharmacol.Exp.Therap., 272:300-309; People such as Thompson, 1995, Proc.Natl.Acad.Sci.USA, 92:7667-7671); 3-bicyclo-[2,2,1] heptan-5-alkene-2-base-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide (people such as Yamada, 1993, J.Neurosc.13:3904-3915); 7-fluoro-3-methyl-5-ethyl-1,2,4-benzothiadiazine-S, S-dioxide; And the chemical compound described in U.S. Patent number 6,620,808 and International Patent Publication No. WO 94/02475, WO 96/38414, WO 97/36907, WO 99/51240 and the WO 99/42456); Benzodiazepine (BZD)/GABA receptor complex regulator (for example Pu Luojia amine, gengabine, Zaleplon and U.S. Patent number 5,538,956,5,260,331 and 5,422, the chemical compound described in 355); 5-hydroxytryptamine antagonist (for example, non-5-HT 1A5-HT receptor modulators (the non-5-HT of antagonist 1AThe example of the 5-HT receptor modulators of antagonist comprises 5-HT6 antagonist (at U.S. Patent number 6,727, having described the non-limiting instance of these chemical compounds in 236,6,825,212,6,995,176 and 7,041,695) without limitation)); (for example nicotinic acid) of nicotine type nicotinic; (for example xanomeline, CDD-0102, cevimeline, Talsaclidine, oxibutynin (oxybutin), tolterodine, propiverine, hydrochloric acid trospium chloride and the darifenacin) of muscarinic type; Monoamine oxidase B (MAO B) inhibitor (for example rasagiline, selegiline, Prey Neil, lazabemide, husky non-amide, clorgiline, pargyline, N-(2-amino-ethyl)-4-chlorobenzoyl amine hydrochlorate and N-(2-amino-ethyl)-5-(3-fluorophenyl)-4-thiazole carboxamides hydrochlorate); Phosphodiesterase (PDE) inhibitor (PDE IV inhibitor for example, roflumilast, arofylline, cilomilast, rolipram, RO-20-1724, theophylline, denbufylline, ARIFLO, CDP-840 (triaryl ethane), CP80633 (pyrimidone), RP 73401 (Rhone-Poulenc Rorer), denbufylline (SmithKline Beecham), arofylline (Almirall company), CP-77,059 (Pfizer), pyrido [2,3-d] pyridazines-5-ketone (Syntex company), EP-685479 (Beyer Co., Ltd), T-440 (Tanabe Seiyaku) and SDZ-ISQ-844 (Novartis Co.,Ltd)); G albumen; Channel modulators; Immunotherapeutic agent (for example, the chemical compound described in U.S. Patent Application Publication No. US2005/0197356 and the US 2005/0197379); Anti-amyloid medicine or fall amyloid medicine (for example chemical compound described in a crust pearl monoclonal antibody and U.S. Patent number 6,878,742 or U.S. Patent Application Publication No. US 2005/0282825 or the US 2005/0282826); Statins and peroxisome proliferation-activated receptors (PPARS) regulator (gemfibrozil for example
Figure A200780020562D00201
Fenofibrate
Figure A200780020562D00202
Rosiglitazone maleate
Figure A200780020562D00203
Pioglitazone (Actos TM), rosiglitazone (Avandia TM), clofibrate and bezafibrate); The cysteinyl protease inhibitor; Advanced glycosylation end product receptor (RAGE) inhibitor (for example aminoguanidine, pyridoxamine carnosine, azophenlyene diamidogen, OPB-9195 and tenilsetam); Direct or indirect (for example, has a liking for neurotic
Figure A200780020562D00211
Piracetam, oxiracetam, AIT-082 (Emilieu, 2000, Arch.Neurol.57:454)); Beta-secretase (BACE) inhibitor; Alpha-secretase enzyme, the activator of having a liking for immunizing agent, caspase-3 inhibitor, Src inhibitors of kinases, tissue plasminogen activator (TPA), AMPA (alpha-amido-3-hydroxy-5-methyl base-4-isoxazole propanoic acid) regulator, M4 agonist, JNK3 inhibitor, lxr agonist, H3 antagonist and angiotensin 5 antagonist.Other cognitive enhancer comprise without limitation: acetyl-1-carnitine, citicoline, huperzine, DMAE (dimethylaminoethanol), false portulaca oleracea extracts, sage extract, L-Alpha-Glyceryl Phosphorylcholine, Semen Ginkgo and Semen Ginkgo extrac, vinpocetine, DHA, nootropics, comprise phenyl methylatropine bromide (Phenyltropin), Pikatropin is (from Creative Compounds, LLC, Scott City, MO), besipirdine, linopirdine, sibopirdinum, estrogen and estrogen compound, idebenone, T-588 (Toyama Chemical, Japan) and FK960 (rattan pool pharmaceutical Co. Ltd (Fujisawa)).U.S. Patent number 5,219,857,4,904,658,4,624,954 and 4,665, the chemical compound described in 183 is also as cognitive enhancer as herein described.The cognitive enhancer that works by above one or more mechanism also is covered by within the scope of the present invention.
[0019] relates to " providing " as used herein when chemical compound that the present invention contains or material are provided and be meant and directly use this chemical compound or material, perhaps use the chemical compound that can form equivalent in vivo or prodrug, derivant or the analog of material.Prodrug can be prepared according to following document is described: Prodrug design (Design of Prodrugs), Bundgaard, H. edits, (Elsevier, New York 1985); Prodrug (Prodrugs as Novel Drug as new drug delivery system Delivery Systems), Higuchi, T and Stella, V. edits, (American Chemical Society (AmericanChemical Society), Washington, District of Columbia 1975); By prodrug and analog Design biopharmaceutics character (Design of Biopharmaceutical Properties through Prodrugs and Analogs), Roche, E. edits, (association of pharmacists of U.S. pharmacy association, Washington, District of Columbia 1977); And Balant, L.P. and Doelker, E., " metabolic consideration (Metabolic Considerations in Prodrug Design) in the prodrug design ", Burger ' s Medicinal Chemistry and Drug DiscoveryIn, the 5th edition, Wolff, M. edits, volume 1,49-982 page or leaf (John Wiley ﹠amp; Sons, Inc.1995).
[0020] chemical compound as described herein comprises 5-HT 1AAgonist compounds and cognitive enhancer are used to prepare the medicine that is used for treating cognitive disorder or is used for strengthening cognition interior.
[0021] As used herein can give scheme of combination drug therapy simultaneously, perhaps can adopt 5-HT on the time different with cognitive enhancer 1AAgonist compounds or 5-HT 1AThe staggered dosage regimen of the pharmaceutical salts of agonist compounds is carried out scheme of combination drug therapy.Time of application difference between described two kinds of medicines can be a few minutes, several hours, several days, a few week or longer scope.Therefore, term " associating " is not necessarily represented administration simultaneously or with same dosage device administration, also can be used each component in the required treatment phase.These medicines also can pass through different administrations.For example, in the combination of 5-HT1A agonist compounds or its pharmaceutical salts and cognitive enhancer, expection will be used 5-HT with oral or parenteral mode 1AAgonist compounds or its pharmaceutical salts, and cognitive enhancer can be used by parenteral, oral or other acceptable manner.Described combination can be per hour, every day, weekly or even once used in every month.
Should be understood that [0022] dosage of each component in the scheme of combination drug therapy can be according to used particular compound, administering mode, the disease of being treated and seriousness thereof and the various physical factors relevant with the individuality of being treated and different.In addition, should be appreciated that the effective dose of this combination can be according to used particular compound, administering mode, the disease of being treated and seriousness thereof and the various physical factors relevant with the individuality of being treated and different.
[0023] 5-HT 1AAgonist compounds or 5-HT 1AThe effective dose of the officinal salt of agonist compounds and the combination of cognitive enhancer is meant the amount of effective treatment or prevention cognitive disorder.In addition, can randomly adopt external or the definite best dosage range of in vivo test help.Used exact dose also can depend on route of administration, the disease of being treated and seriousness thereof and the various physical factors relevant with the individuality of being treated, and can decide according to health doctor's judgement.Can go through and use identical dosage different periods, include but not limited to described period per approximately 2 hours, per approximately 6 hours, per approximately 8 hours, per approximately 12 hours, per approximately 24 hours, per approximately 36 hours, per approximately 48 hours, per approximately 72 hours, approximately weekly, per approximately 2 weeks, per approximately 3 weeks, per 2 months of every month peace treaty approximately.With the complete course of treatment corresponding administration number of times and frequency will determine according to health doctor's judgement.
[0024] as the part of scheme of combination drug therapy, 5-HT 1AThe dosage of the officinal salt of chemical compound or this chemical compound usually in about 0.001mg/kg body weight/day to about 600mg/kg body weight/day, be lower than about 600mg/kg body weight/day in one embodiment, be lower than about 400mg/kg body weight/day in another embodiment, be lower than about 200mg/kg body weight/day in another embodiment, be lower than about 100mg/kg body weight/day in another embodiment, be lower than about 10mg/kg body weight/day in another embodiment, be lower than about 1mg/kg body weight/day in another embodiment, be lower than about 0.5mg/kg body weight/day in another embodiment, be lower than about 0.1mg/kg body weight/day in another embodiment and be lower than about 0.001mg/kg body weight/day in another embodiment.In one embodiment, as the part of scheme of combination drug therapy, 5-HT 1AThe dosage of the officinal salt of chemical compound or this chemical compound is lower than its effective dose when not giving other cognitive enhancer.Therefore, 5-HT 1AThe amount of the officinal salt of chemical compound or this chemical compound is the amount that is lower than under therapeutic dose or the threshold.At this moment, under condition not bound by theory, think 5-HT 1AThe officinal salt and the cognitive enhancer of chemical compound or this chemical compound play a role with cooperative mode.In some cases, need the patient of treatment to treat with one or more other treatment agent.
[0025] amount of cognitive enhancer is generally about 0.001mg/kg body weight/day to about 600mg/kg body weight/day in this combination, be lower than about 600mg/kg body weight/day in one embodiment, be lower than about 400mg/kg body weight/day in another embodiment, be lower than about 200mg/kg body weight/day in another embodiment, be lower than about 100mg/kg body weight/day in another embodiment, be lower than about 10mg/kg body weight/day in another embodiment, be lower than about 1mg/kg body weight/day in another embodiment, be lower than about 0.5mg/kg body weight/day in another embodiment, be lower than about 0.1mg/kg body weight/day in another embodiment, in another embodiment, be lower than about 0.001mg/kg body weight/day.In one embodiment, as the part of scheme of combination drug therapy, the dosage of cognitive enhancer is lower than ought not give 5-HT 1AIts effective dose during the officinal salt of chemical compound or this chemical compound.Therefore, the amount of cognitive enhancer is the amount that is lower than under therapeutic dose or the threshold.At this moment, under condition not bound by theory, think 5-HT 1AThe officinal salt and the cognitive enhancer of chemical compound or this chemical compound play a role with cooperative mode.In some cases, need the patient of treatment to treat with one or more other treatment agent.
[0026] as discussed herein, pharmaceutical dosage form can be to comprise 5-HT 1AAgonist compounds or 5-HT 1AThe pharmaceutical salts of agonist compounds or cognitive enhancer perhaps comprise 5-HT 1AAgonist compounds or 5-HT 1AThe pharmaceutical salts of agonist compounds and the dosage form of cognitive enhancer.Similarly, as discussed herein, pharmaceutical composition can be that separated drug or two kinds of medicines coexist in a kind of compositions.
[0027] in one embodiment, pharmaceutical composition is a unit dosage form, for example tablet, capsule, powder, solution, suspensoid, Emulsion, granule or suppository.In this form, compositions is subdivided into the unit dose that contains an amount of active component; Unit dosage form can be packaged compositions, for example, and packaged powders, bottle, ampoule, prefilled syringe or contain the sachet of liquid.Unit dosage form itself can be for example capsule or tablet, and perhaps it can be any of these compositions of the right quantity of packaged form.Described unit dosage form can contain the 5-HT of 0.001mg/kg to about 250mg/kg that have an appointment 1AThe officinal salt of chemical compound or this chemical compound, and can use with single dose or with two or more fractionated doses.Similarly, this unit dosage form can contain the extremely cognitive enhancer of about 250mg/kg of 0.001mg/kg of having an appointment, and can use with single dose or with two or more fractionated doses.Dosage will inevitably change to the individual reaction of medicine according to treatment patient's species, body weight and situation and patient.
[0028] in one embodiment, unit dosage form is about 5-HT of 0.001 to about 1000mg 1AAgonist compounds or 5-HT 1AThe officinal salt of agonist compounds.In another embodiment, unit dosage form is about 0.01 to about 500mg; In another embodiment, unit dosage form is about 0.01 to about 250mg; In another embodiment, unit dosage form is about 0.01 to about 100mg; In another embodiment, unit dosage form is about 0.01 to about 50mg; In another embodiment, unit dosage form is about 0.01 to about 25mg; In another embodiment, unit dosage form is about 0.01 to about 10mg; In another embodiment, unit dosage form is about 0.01 to about 5mg; In another embodiment, unit dosage form is about 0.01 to about 10mg.
[0029] in one embodiment, unit dosage form is about cognitive enhancer of 0.001 to about 1000mg.In another embodiment, unit dosage form is about 0.01 to about 500mg; In another embodiment, unit dosage form is about 0.01 to about 250mg; In another embodiment, unit dosage form is about 0.01 to about 100mg; In another embodiment, unit dosage form is about 0.01 to about 50mg; In another embodiment, unit dosage form is about 0.01 to about 25mg; In another embodiment, unit dosage form is about 0.01 to about 10mg; In another embodiment, unit dosage form is about 0.01 to about 5mg; In another embodiment, unit dosage form is about 0.01 to about 10mg.
[0030] when to animals administer, the officinal salt of described chemical compound or chemical compound can merely be used or use as the component that comprises the compositions of physiologically acceptable carrier or excipient.Can use and comprise the officinal salt of described chemical compound or chemical compound and the method for physiologically acceptable carrier, excipient or mixing diluents are prepared pharmaceutical composition of the present invention.Can be by the officinal salt of described chemical compound or chemical compound be realized mixing with the known method of physiologically acceptable carrier, excipient or mixing diluents.
[0031] comprising this pharmaceutical composition of the officinal salt of chemical compound of the present invention or chemical compound can the oral administration administration.Chemical compound of the present invention also can be by any other administration easily, for example by infusion or inject, by epithelium or mucocutaneous in (for example by oral cavity, rectum, vagina and intestinal mucosa etc.) absorb, and can be with another kind of therapeutic agent administration.Can whole body administration or topical.Can use various known delivery systems, comprise be encapsulated in the liposome, microgranule, microcapsule and capsule.
[0032] medication include but not limited in Intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, Sublingual, the brain, intravaginal, percutaneous, rectum, by sucking or the topical of topical, particularly ear, nose, eye or skin.In some cases, administration will cause the officinal salt of chemical compound or chemical compound to be released into blood flow.Administering mode is considered by the doctor.
[0033] in one embodiment, chemical compound of the present invention passes through oral administration.
[0034] in another embodiment, chemical compound of the present invention passes through intravenous administration.
[0035] in another embodiment, can take local application chemical compound of the present invention.For example can be in the intra-operative local infusion, for example operation back and the common local application of wound dressing, by injection, by conduit, realize by suppository or enema or by implant, described implant is porous, atresia or gelatinous material, and it comprises for example silicone rubber (sialastic) film or fibrous membrane.
[0036] in certain embodiments, can chemical compound of the present invention be introduced central nervous system, blood circulation or gastrointestinal tract by any suitable way, comprise that Intraventricular, intrathecal injection, spinal column sidenote are penetrated, epidural injection, coloclysis and near peripheroneural injection.For example, can help to carry out intracerebral ventricle injection by the intraventricular catheter that links to each other with storage such as ommaya reservoir (Ommaya reservoir).
[0037] also can perhaps carry out pulmonary administration for example with inhaler or aerosol apparatus and preparation with aerosol by the infusion liquid in fluorocarbon or synthetic Curosurf.In certain embodiments, the officinal salt of chemical compound or chemical compound can be made suppository with conventional binding agent and excipient such as triglyceride.
[0038] in another embodiment, chemical compound of the present invention can send by vesicles, particularly liposome (referring to Langer, Science 249: people such as 1527-1533 (1990) and Treat, the liposome in infectious disease and treatment of cancer (Liposomes in the Therapy of InfectiousDisease and Cancer) 317-327 and 353-365 (1989)).
[0039] in the another one embodiment, chemical compound of the present invention can send by controlled release system or slow-released system (referring to, Goodson for example, the medical application of controlled release (Medical Applicationsof Controlled Release), volume 2,115-138 page or leaf (1984)).Can use at Langer Science 249: other controlled releases or the slow-released system discussed in the summary of 1527-1533 (1990).In one embodiment, can use pump (Langer, Science 249: 1527-1533 (1990); Sefton, CRCCrit.Ref.Biomed.Eng. 14: 201 (1987); People such as Buchwald, Surgery 88: 507 (1980); With people such as Saudek, N.Engl.JMed. 321: 574 (1989)).In another embodiment, can use polymeric material (referring to the medical application (Medical Applicationsof Controlled Release) (Langer and Wise edit, 1974) of controlled release; Controlled drug bioavailability, medicine design and put into practice (Controlled Drug Bioavailability, Drug Product Designand Performance) (Smolen and Ball edit, 1984); Ranger and Peppas, J.Macromol.Sci.Rev.Macromol.Ch em. 2: 61 (1983); People such as Levy, Science 228: 190 (1935); People such as During, Ann.Neural. 25: 351 (1989); With people such as Howard, J.Neurosurg. 71: 105 (1989)).
[0040] compositions of the present invention can randomly comprise an amount of physiologically acceptable excipient.
[0041] described physiologically acceptable excipient can be a liquid, and for example water and oil comprise oil, animal oil, vegetable oil or synthetic oil, for example Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, Semen Sesami wet goods.Physiologically acceptable excipient can be saline, arabic gum, gelatin, gelatinized corn starch, Pulvis Talci, keratin, silica sol, carbamide etc.In addition, can use adjuvant, stabilizing agent, thickening agent, lubricant and coloring agent.In one embodiment, when to animals administer, described physiologically acceptable excipient is aseptic.Described physiologically acceptable excipient should be stable under manufacturing and storage requirement, and should prevent preservation under the microbial contamination.When the officinal salt of chemical compound or chemical compound passed through intravenous administration, water was useful especially excipient.The aqueous solution of saline solution and glucose and glycerol also can be used as liquid excipient, especially for injection.Suitable physiologically acceptable excipient also comprises starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Pulvis Talci, sodium chloride, defatted milk powder, glycerol, propylene glycol, water, ethanol etc.If necessary, said composition also can contain a spot of wetting agent or emulsifying agent or pH buffer agent.
[0042] liquid-carrier can be used for preparing solution, suspensoid, Emulsion, syrup and elixir.The officinal salt of chemical compound of the present invention or chemical compound can dissolve or be suspended in pharmaceutically useful liquid-carrier such as water, organic solvent, both mixture or pharmaceutically useful oil or fat.Described liquid-carrier can contain other suitable medical additives, comprises solubilizing agent, emulsifying agent, buffer agent, antiseptic, sweeting agent, correctives, suspending agent, thickening agent, coloring agent, viscosity modifier, stabilizing agent or osmotic pressure regulator.The example that is fit to the liquid-carrier of oral or parenteral comprises that water (particularly contains aforesaid additive, cellulose derivative for example, comprise carboxymethylcellulose sodium solution), alcohols (comprises monohydric alcohol and polyhydric alcohol, glycol for example) and derivant, and oils (for example, fractionated coconut oil and Oleum Arachidis hypogaeae semen).The carrier that is used for parenteral also can be grease, for example ethyl oleate and isopropyl myristate.In the aseptic fluid composition of parenteral, use sterile liquid carrier.The liquid-carrier that is used for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically useful propellant.
[0043] compositions of the present invention can adopt form or any other suitable form of using of solution, suspensoid, Emulsion, tablet, pill, piller, capsule, the capsule that comprises liquid, powder, slow releasing preparation, suppository, Emulsion, aerosol, spray, suspensoid.In one embodiment, compositions is a capsule form.The example of other suitable physiologically acceptable excipient has been described in Remington ' s Pharmaceutical Sciences1447-1676 (Alfonso R.Gennaro edits, the 19th edition, 1995).
[0044] in one embodiment, the officinal salt of chemical compound or chemical compound is made the compositions that is suitable for to the human oral administration according to the method for routine.For example, the compositions of oral delivery can be the form of tablet, lozenge, buccal, buccal tablet, water or oil suspension or solution, granule, powder, Emulsion, capsule, the capsule that comprises liquid, syrup, aerosol, spray or elixir.Liquid preparations for oral administration can contain one or more reagent, for example, and sweeting agent such as fructose, aspartame or glucide; Correctives such as lavender, wintergreen oil or Fructus Pruni pseudocerasi; Coloring agent; And antiseptic, thereby provide good to eat pharmaceutical preparation.In powder, carrier can be pulverizing solid, and it is the mixture with the officinal salt of pulverizing chemical compound or chemical compound.In tablet, the officinal salt of described chemical compound or chemical compound with have necessary constrictive carrier and mix mutually with proper ratio and be pressed into desired shape and size.Powder and tablet can contain at most about 99% the chemical compound or the officinal salt of chemical compound.
[0045] capsule can contain the mixture of the officinal salt of described chemical compound or chemical compound and inert filler and/or for example pharmaceutically acceptable starch of diluent (for example corn, Rhizoma Solani tuber osi or tapioca), sugar, artificial sweetener, Powderd cellulose (for example crystalline cellulose and microcrystalline Cellulose), flour, gelatin, natural gum etc.
[0046] tablet can be by conventional compacting, wet method or dry granulation method preparation, and use acceptable diluents, binding agent, lubricant, disintegrating agent, surface modifier (comprising surfactant), suspending agent or stabilizing agent (include but not limited to magnesium stearate, stearic acid, sodium lauryl sulphate, Pulvis Talci, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline Cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, arabic gum, xanthan gum, sodium citrate, composition silicate, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, Kaolin, mannitol, sodium chloride, low melt wax and ion exchange resin).Surface modifier comprises non-ionic and anionic surface modifier.The representative example of surface modifier includes but not limited to poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, silica sol, phosphate, sodium lauryl sulphate, aluminium-magnesium silicate and triethanolamine.
[0047] in addition, when taking tablet or pill, compositions can be carried out coating with disintegrate and the absorption of delay in gastrointestinal tract, thereby provides lasting effect in the period that prolongs.The permoselective membrane that surrounds the officinal salt that is subjected to chemical compound that osmotic pressure drives or this chemical compound also is suitable for Orally administered compositions.In the latter's platform, can draw liquid by driving chemical compound from the capsule surrounding, latter's swelling is replaced this composition or component composition by aperture.These delivery platforms can provide the delivery curves that is essentially zero level, and are opposite with the crest curve of IR formulation.Also can use the time-delay material, for example glyceryl monostearate or glyceryl stearate.Orally administered composition can comprise standard excipients, as mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose and magnesium carbonate.In one embodiment, excipient is a pharmaceutical grade.
[0048] in another embodiment, the officinal salt of described chemical compound or chemical compound can be prepared and be used for intravenous administration.Usually, the compositions of intravenous administration comprises the sterile isotonic water-containing buffering liquid.If be necessary that compositions also can comprise solubilizing agent.The compositions of intravenous administration can randomly comprise local anesthetic, as lignocaine, to alleviate the pain of injection site.Generally speaking, each composition is separated to provide or is blended in the unit dosage form, for example at sealed container as the ampoule or the freeze-dried powder in the medicine bag (sachette) that are indicating active principle or there is not aqueous concentrate.If the officinal salt of chemical compound or this chemical compound can be with it with for example containing the preparation of aseptic pharmaceutical grade water or brinish infusion bottle by the infusion administration.If the officinal salt of chemical compound or this chemical compound can provide sterile water for injection or brinish ampoule, so that can mix each composition before administration by drug administration by injection.
[0049] in another embodiment, the officinal salt of described chemical compound or this chemical compound can utilize the transdermal patch transdermal administration.Transdermal administration comprises the administration that sees through body surface and comprise the body passageway internal layer of epithelium and mucosal tissue.This class administration can use lotion, cream, foam, patch, suspensoid, solution and the suppository (for example rectum or vaginal suppository) of the officinal salt of described chemical compound or chemical compound to carry out.
[0050] transdermal administration can utilize the officinal salt that contains described chemical compound or chemical compound and the transdermal patch of carrier to finish, this carrier to the officinal salt of described chemical compound or chemical compound be inertia, nontoxic and allow medicine to absorb to enter blood flow to skin via integumentary system.Carrier can be taked arbitrary form, as cream or ointment, paste, gel or locking device.Cream or ointment can be viscous liquid or oil-in-water or the semi-solid Emulsion of water-in-oil type.By being dispersed in oil or the hydrophilic petroleum, containing the paste that the absorbent powder of active component forms and also may be fit to.Multiple closure device can be used for the officinal salt of chemical compound or this chemical compound is released into blood flow, for example covers to contain the officinal salt of chemical compound or this chemical compound and contain or the semipermeable membrane of carrier-free bank, perhaps contains the substrate of active component.
[0051] officinal salt of chemical compound of the present invention or this chemical compound can carry out rectum or vagina administration with conventional suppository form.Suppository can be made with conventional material, comprises cocoa butter, adding or does not add the wax class to change the fusing point and the glycerol of suppository.Also can use water soluble suppository bases, as various molecular weight polyethylene glycol.
[0052] officinal salt of described chemical compound or this chemical compound can pass through the known controlled release of those of ordinary skills or slow release means or delivery apparatus administration.This class dosage form can be used to provide the controlled release or the slow release of one or more active component, it uses for example hydroxypropyl emthylcellulose, other polymeric matrixs, gel, osmotic membranes, osmosis system, multiple coatings, microgranule, liposome, microsphere or its combination by different proportion, so that required release profiles to be provided.Can easily select suitable controlled release well known by persons skilled in the art or slow releasing preparation, comprise those preparations described herein, be used for active component of the present invention.Therefore, the single unit dosage forms that is suitable for oral administration has been contained in the present invention, such as but not limited to the tablet that is suitable for controlled release or slow release, capsule, soft capsule and Caplet (caplet).
[0053] in one embodiment, controlled release or slow releasing composition comprise the chemical compound of minimum or the officinal salt of chemical compound, with the shortest time internal therapy or the prevention cognitive disorder.The advantage of controlled release or slow releasing composition comprises the compliance of the animal that prolong drug activity, reduction administration frequency and increase are received treatment.In addition, controlled release or slow releasing composition can advantageously influence onset time or other character, the blood drug level of the officinal salt of chemical compound or chemical compound for example, and can therefore reduce the generation of adverse side effect.
[0054] controlled release or slow releasing composition can discharge a certain amount of rapid generation expection treatment or the chemical compound of preventive effect or the officinal salt of chemical compound at first, and little by little and constantly discharge the chemical compound of its surplus or the officinal salt of chemical compound, thereby in the period that prolongs, keep the level of this treatment or preventive effect.Constant level for the officinal salt of keeping chemical compound in the body or chemical compound, the officinal salt of chemical compound or chemical compound discharges from dosage form with given pace, and the officinal salt that this speed can substitute described chemical compound or chemical compound is by metabolism and the amount that goes out from body excretes.By various conditions, include but not limited to change, the temperature of pH, concentration or availability, the concentration of water or the change of availability or other physiological conditions or chemical compound of enzyme, controlled release or slow release that can the stimulating activity composition.
[0055] in certain embodiments, the present invention relates to the prodrug of compound or pharmaceutically acceptable salt thereof of the present invention.The various forms of prodrug is known in the art, Bundgaard (editor) for example, prodrug design (Design of Prodrugs), Elsevier (1985); People such as Widder (editor), Enzymology method (Methods in Enzymology), volume 4, Academic Press (1985); People such as Kgrogsgaard-Larsen (editor), " design of prodrug and application (Design andApplication of Prodrugs) ", Textbook of Drug Design and Development, the 5th chapter, 113-191 (1991); People such as Bundgaard, Journal of Drug Delivery Reviews, 8:1-38 (1992); People such as Bundgaard, J.Pharmaceutical Sciences, 77:285 is with reference to following (1988); With Higuchi and Stella (editor), as the prodrug (Prodrugs as Novel Drug Delivery Systems) of new drug delivery system, described in the American Chemical Society (AmericanChemical Society) (1975).
[0056] in one aspect, the present invention includes and contain 5-HT 1AAntagonist and cognitive enhancer be as the medicine of combination preparation, is used for simultaneously, respectively or successively make and be used for treating cognitive disorder.On the other hand, the present invention includes 5-HT 1AAntagonist and the cognitive enhancer purposes in the medicine of preparation treatment cognitive disorder.In yet another aspect, the present invention includes cognitive enhancer at preparation and 5-HT 1APurposes in the medicine of the treatment cognitive disorder of antagonist coupling.In yet another aspect, the present invention includes 5-HT 1AThe purposes of antagonist in the medicine of the treatment cognitive disorder of preparation and cognitive enhancer coupling.
Embodiment
[0057] illustrates the present invention by reference following examples and additional information.The embodiment of the experiment that provides is only presented for purposes of illustration.It should not be interpreted as limiting the scope of the invention by any way or content.The technical staff in organic synthesis field can know the route of other synthetic The compounds of this invention in addition.Reagent used herein and intermediate are by commercial that buy or according to the preparation of the literature method of standard.
[0058] method of test The compounds of this invention to the effect of cognitive dysfunction described hereinafter.These methods are used to identify the 5-HT of effective treatment cognitive disorder 1AAntagonist (that is 5-HT, 1AReceptor antagonist) and cognitive enhancer.Other test compounds are known in the art to the method for the effect of cognitive dysfunction, and for example comprise following experimental technique: background or hint sex dread trained reflex (Comery, T.A. wait the people, Journal of Neuroscience 25 (39): 8898-8902 (on JIUYUE 28th, 2005)), passive avoidance (Foley, A.G. wait the people, Neuropsychopharmacology 29:93-100 (2004)), radiation arm labyrinth (Boast, C. wait the people, Neurobiology of Learning andMemory 71:259-271 (1999)), Mo Lisi water maze (Day, M. and Langston, R.F., Neuroscience 137:19-28 (2006)) and the serial reaction task (Robbins of 5 kinds of selections, T.W., Psychopharmacology 163:362-380 (2002)).
Embodiment 1
Cognitive enhancing-Xin object identification
[0059] treats the mild cognitive defective that causes by Alzheimer with acetylcholinesteraseinhibitors inhibitors at present.Yet the common adverse effect of this class therapeutic agent has hindered the application of acetylcholinesteraseinhibitors inhibitors, and effect is limited.5-HT 1AAntagonist (5-fluoro-4-methoxyl group-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl)-2-(trifluoromethyl) quinoline and 5-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline) demonstrates representational acetylcholinesteraseinhibitors inhibitors
Figure A200780020562D00321
Strengthen cognitive character and have cooperative effect, reduced by two kinds of reagent and in new object identification model, obtained the required dosage of effect.
[0060] New object identification model: male Long-Evans scarf rat (about 200g during test) is fed separately, the drinking-water of arbitrarily ingesting.(diameter～70cm, high 30cm) carries out new object cognition (NOR) training and testing at the border circular areas that is made of and contains soil bedding (no feces) plastics.This zone is centered on by the black curtain, with the shielding area other factor, and is positioned at and has white noise (～65dB) concealed light chamber (illumination level～10lux).The performance of video tracking animal, and by the experimenter's monitoring that is positioned at outside the test room.By
Figure A200780020562D00322
The object of piece (Lego) structure can be fixed on one of four positions of even interval, the about 10cm in distance areas edge on this floor, zone.For fear of possible olfactory sensation factor, during whole research, between animal, use a plurality of object copies also to clean with 30% alcoholic solution.
[0061] visual identity task be divided into 3 the period-custom formation, sampling test and selection test.During custom forms, be positioned over animal in the place of containing 2 identical yellow cubes (～10cm x 10cm x10cm) and allow animal to detect the place 10 minutes.After custom formed, rat returned its cage house.Custom forms back 1 day, to animals administer (5-HT 1AAgonist compounds, cognitive enhancer or 5-HT 1AAgonist compounds and cognitive enhancer), and begin sampling test after the interval behind pretreat.During sampling test, allow rat to detect and contain 2 identical stimulus object (the Duplo object complicated, multicolour that is positioned at relative compass heading at present;～10cm x 10cmx 10cm) place 5 minutes.Note the time of detecting object in the whole test.Detect be defined as rat nose apart from object in the 2cm scope.After the sampling test, rat returns the interval that its cage house is stayed 48 hours test bay, the cognitive memory of test in selecting test then.Select test to comprise that 5 minutes places detect, contain familiar objects and the new object before detected in the place, research worker writes down probe time once more.At custom formation, sampling test and selection duration of test, isostatic object's position keeps constant with regard to every animal between the treatment group.
[0062] with single factor ANOVA to testing total time of contact, the therapeutic effect of using Fisher ' s LSD cell mean Paired comparison method check to detect then at the duration of test object.With the ANOVA of repeated measure, use Fisher ' s LSD postmortem analysis matching type to analyze the time of detecting new object and familiar objects between the treatment group then.Detect new object than the more time that the object of being familiar with significantly spends, show the complete recognition memory of treatment group.Contrast and do not treat animal 48 hours delay after the object of being familiar with and newly object do not demonstrate significant difference between detecting, show sampling test memoryless (significant difference is meant obviously have shorter delay).
[0063] with sub-threshold dose (recognition memory not being provided the dosage of positive effect)
Figure A200780020562D00331
And 5-HT 1AAgonist compounds is applied to experimental animal, and by its effect to recognition memory of above-mentioned record.
[0064] Treatment: before sampling test, used 5-HT in 60 minutes 1AAgonist compounds treatment animal.Be dissolved in the suitable solvent each candidate compound and oral administration.Then before sampling test 30 minutes with
Figure A200780020562D00332
Treat same animal.Will
Figure A200780020562D00333
Be dissolved in the suitable solvent also by the intraperitoneal administration.
[0065] gives sub-threshold dose separately to animal
Figure A200780020562D00334
(0.5mg/kg, intraperitoneal) or 5-HT 1AAgonist compounds (0.1mg/kg, oral).When individually dosed, animal does not have the difference (P＜0.05) on the statistics time of contact in that be familiar with and new environment.Co-administered
Figure A200780020562D00335
Various 5-HT with same dosage 1AAgonist compounds has caused in the different dosing test of various medicines and time of contact statistically the remarkable increase (P＜0.05) of environment facies ratio in new environment of being familiar with.The increase average out to of time of contact was more than 10 seconds.These data show 5-HT 1AThe administering drug combinations of agonist compounds and cognitive enhancer has caused the positive role to recognition memory, this point by animal detect new object ratio detect familiar objects spend significantly the longer time proved.5-HT has been identified in this test of these digital proofs effectively 1AThe cooperative effect of the enhancing cognition between agonist compounds and the cognitive enhancer.These data also prove 5-HT 1AThereby agonist compounds and cognitive enhancer play a role synergistically and improve cognition.
[0066] embodiment that provides more than has illustrated and can be used to test the method that trial drug as herein described improves the ability of cognitive dysfunction.Can use other models that is used to test cognitive dysfunction known in the art.
Embodiment 2
Use 5-HT 1A Antagonist (R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyrrole The pyridine base) cognition of cyclohexane carboxamide strengthens
[0067] use the new object identification method described in the embodiment 1 to measure cognitive the enhancing.But, some changes are arranged.For example, 5-HT 1AAntagonist, i.e. (R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide (chemical compound 405) uses with the dosage of 0.3mg/kg the weight of animals.In addition, the pretreat phase of chemical compound 405 is 120 minutes, rather than 60 minutes.
[0068] result shows, with the Mus of vehicle treated, independent using The Mus of handling, separately with the Mus of chemical compound 405 processing with comprising
Figure A200780020562D00342
And between the Mus of the therapeutic alliance of chemical compound 405 processing, the probe time of Mus similar relatively (Fig. 1).With comprising
Figure A200780020562D00343
The Mus of handling with the therapeutic alliance of chemical compound 405 shows the reservation and the identification (Fig. 2) of remarkable improvement.When being exposed to familiar environment, and with solvent or with individually dosed
Figure A200780020562D00344
Or the group that chemical compound 405 is handled compares, and the therapeutic alliance group shows as and reduces (Fig. 2) time of contact statistically significantly.
Embodiment 3
External activity
[0069] following experimental program has proved that effectively candidate compound is in conjunction with 5-HT 1AThe ability of receptor.This experimental program is the antagonism of valid certificates candidate compound also.
Cell line
People 5-HT from the human genomic library had been described [0070] 1AThe PCR of receptor subtype clone people such as (, Mol.Pharmacol., 43:516 (1993)) Chanda.In this research, use expressing human 5-HT 1AStable Chinese hamster ovary line (the h5-HT of receptor subtype 1A.CHO cell).Cell culture is in the DMEM that has replenished 10% hyclone, non essential amino acid and penicillin/streptomycin.
The radioligand combination
[0071] press people such as Dunlop, J., carry out radioligand in conjunction with test described in the J.Pharmacol.and Toxicol.Methods 40:47-55 (1998), the document is incorporated herein by reference.Cell converges to 95-100% with monolayer growth, and collection membrane is used in conjunction with research afterwards.Scrape cell lightly from culture dish, move to centrifuge tube, and at buffer (50mM Tris; PH7.5) centrifuge washing 2 times (2000rpm, 10 minutes, 4 ℃) in.With gained precipitate aliquot and place-80 ℃.Testing the same day, cell thaws on ice and is suspended in the buffer again.Use [ 3H] 8-OH-DPAT studies as radioligand.On 96 hole microtitration plates, in being the buffer of 250 μ L, final total volume carries out the combination test.Implement competitive assay with the unmarked medicine of 7 variable concentrations and the part final concentration of 1.5nM.In the presence of 10 μ M5HT, measure non-specific binding.With the 0.3-30nM concentration range [ 3H] 8-OH-DPAT carries out saturation analysis.After at room temperature hatching 30 minutes, add ice-cold buffer cessation reaction, and (Gaithersburg filters fast by 30 minutes GF/B filter of pre-preg in 0.5% polymine MD) to use the M-96Brandel cell harvestor.
The measurement of cAMP
[0072] by above Dunlop, people such as J. are described to measure.By being hatched at 37 ℃ with the DMEM that contains 25mM HEPES, 5mM theophylline and 10 μ M pargylines, tested in 20 minutes in cell.Handle cell, immediately use test compounds (6 kinds of variable concentrations) to handle cell again to come the Function of Evaluation activity in 10 minutes with Fu Sikelin (final concentration 1 μ M) at 37 ℃.In independent experiment, the antagonist of 6 kinds of concentration preincubate 20 minutes all before adding 10nM 8-OH-DPAT and Fu Sikelin.By removing culture medium and adding the cold test buffer cessation reaction of 0.5ml.Culture dish is assessed the formation of cAMP subsequently-20 ℃ of storages by cAMP SPA algoscopy (peace agate West Asia company (Amersham)).
[0073] this experimental program has been identified effectively and has been had 5-HT 1AAgonist activity and 5-HT 1AThe chemical compound of antagonistic activity.Proved 5-HT by suppressing Fu Sikelin-inductive cAMP level increase 1AAgonist activity, its result is with EC 50Value representation.Has 5-HT 1AThe chemical compound of antagonist activities does not have influence to Fu Sikelin-inductive cAMP level increases, but has blocked the inductive inhibitory action to Fu Sikelin-inductive cAMP level increase of 8-OH-DPAT-.The result is expressed as IC 50Value.
Embodiment 4
Functional activity in the body
[0074] chemical compound is as 5-HT 1AThe ability that antagonist plays a role in vivo can be assessed (D.Blackman with the fixated response model of rat, " trained reflex of operation: behavioral experiment analysis (Operant Conditioning:An Experimental Analysis of Behavior) " J.Butcher edits, Methuen and Co., Ltd., London).In this model, trained rat is presented replying under the plan at 30 kinds of foods of fixed proportion, to reach the reinforcing stimulus of food piller.5-HT 1AThe administration of agonist 8-OH-DPAT has reduced control response rate (estimating by giving the solvent placebo).The 5-HT of testing compound 1AAntagonist activities is measured the antagonistic ability that the response rate of agonist induction reduces by measuring it.Testing compound reverse fully agonist induction response rate, make it get back to the control level to be regarded as antagonist action completely.Therefore, this test can be used to estimate testing compound as 5-HT 1AThe ability that antagonist plays a role in vivo.
Other embodiments
[0075] the present invention can implement with other particular forms under the condition that does not deviate from its purport and base attribute, therefore, should state scope of the present invention with reference to appending claims rather than description above.

Claims (54)

1. the method for treatment cognitive disorder in its patient of needs, this method comprises the 5-HT that uses cooperative effective quantity to the patient 1AAgonist compounds and cognitive enhancer.
2. the method for claim 1, wherein said cognitive disorder are dementia, parkinson disease, Huntington Chorea, Alzheimer, cognitive defect, mild cognitive impairment or the schizophrenia relevant with Alzheimer.
3. the method for claim 1, wherein 5-HT 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide or its pharmaceutically useful acid-addition salts,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide or its pharmaceutically useful acid-addition salts,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide or its pharmaceutically useful acid-addition salts,
5-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline or its pharmaceutically useful acid-addition salts, or
5-fluoro-4-methoxyl group-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl)-2-(trifluoromethyl) quinoline or its pharmaceutically useful acid-addition salts.
4. method as claimed in claim 3, wherein 5-HT 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline or its pharmaceutically useful acid-addition salts,
5-fluoro-4-methoxyl group-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl)-2-(trifluoromethyl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
8-{4-[4-(1H-indole-4-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-{4-[4-(5-fluoro-benzofuran-3-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
7-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-(4-(1-(quinoline-8-ylmethyl) piperidin-4-yl) piperazine-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-5-fluoroform yl-quinoline and pharmaceutically useful acid-addition salts thereof,
5-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-[4-(4-quinoline-8-base-piperazine-1-yl)-piperidines-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof, or
8-[4-(4-benzofuran-3-base-piperazine-1-yl)-piperidines-1-yl]-6-chloro-quinoline and pharmaceutically useful acid-addition salts thereof.
5. as any described method, wherein a 5-HT in claim 3 or 4 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide or its pharmaceutically useful acid-addition salts,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide or its pharmaceutically useful acid-addition salts,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide or its pharmaceutically useful acid-addition salts,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof, or
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
6. as any described method, wherein a 5-HT in the claim 3 to 5 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof, or
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
7. as any described method, wherein a 5-HT in the claim 3 to 6 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof, or
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof.
8. as any described method, wherein a 5-HT in the claim 3 to 7 1AAgonist compounds is
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof.
9. as any described method in the claim 1 to 8, wherein cognitive enhancer is a cholinesterase inhibitor.
10. method as claimed in claim 9, wherein cholinesterase inhibitor is tacrine, donepezil, sharp this bright or galantamine.
11. as any described method in the claim 1 to 8, wherein cognitive enhancer is nmda antagonist or NMDA agonist.
12. as any described method in the claim 1 to 8, wherein cognitive enhancer is the ampakine compounds.
13. as any described method in the claim 1 to 8, wherein cognitive enhancer is a BZD/GABA receptor complex regulator.
14. as any described method in the claim 1 to 8, wherein cognitive enhancer is a 5-hydroxytryptamine antagonist.
15. as any described method in the claim 1 to 8, wherein cognitive enhancer is the nicotine type nicotinic chemical compound.
16. as any described method in the claim 1 to 8, wherein cognitive enhancer is the muscarinic type chemical compound.
17. as any described method in the claim 1 to 8, wherein cognitive enhancer is the MAO-B inhibitor.
18. as any described method in the claim 1 to 8, wherein cognitive enhancer is the PDE inhibitor.
19. as any described method in the claim 1 to 8, wherein cognitive enhancer is the G protein compound.
20. as any described method in the claim 1 to 8, wherein cognitive enhancer is a channel modulators.
21. as any described method in the claim 1 to 8, wherein cognitive enhancer is the immunization therapy compounds.
22. as any described method in the claim 1 to 8, wherein cognitive enhancer is the anti-amyloid medicine or falls the amyloid medicine.
23. as any described method in the claim 1 to 8, wherein cognitive enhancer is Statins or PPARS regulator.
24. as any described method in the claim 1 to 23, wherein this method comprises oral delivery 5-HT 1AAgonist compounds.
25. as any described method in the claim 1 to 24, wherein this method comprises sending of slow release chemical compound.
26. strengthen cognitive method in its patient of needs, this method comprises the 5-HT that uses cooperative effective quantity to the patient 1AAgonist compounds and cognitive enhancer.
27. the pharmaceutical composition of treatment cognitive disorder, said composition comprises 5-HT 1AAgonist compounds and cognitive enhancer.
28. pharmaceutical composition as claimed in claim 27, wherein 5-HT 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline or its pharmaceutically useful acid-addition salts,
5-fluoro-4-methoxyl group-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl)-2-(trifluoromethyl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
8-{4-[4-(1H-indole-4-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-{4-[4-(5-fluoro-benzofuran-3-yl)-piperazine-1-yl]-piperidines-1-yl }-quinoline and pharmaceutically useful acid-addition salts thereof,
7-fluoro-8-(4-(4-(6-methoxy quinoline-8-yl) piperazine-1-yl) piperidines-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-(4-(1-(quinoline-8-ylmethyl) piperidin-4-yl) piperazine-1-yl) quinoline and pharmaceutically useful acid-addition salts thereof,
8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-5-fluoroform yl-quinoline and pharmaceutically useful acid-addition salts thereof,
5-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof,
5-fluoro-8-[4-(4-quinoline-8-base-piperazine-1-yl)-piperidines-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof, or
8-[4-(4-benzofuran-3-base-piperazine-1-yl)-piperidines-1-yl]-6-chloro-quinoline and pharmaceutically useful acid-addition salts thereof.
29. as claim 27 or 28 described pharmaceutical composition, wherein 5-HT 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof, or
6-fluoro-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
Any described pharmaceutical composition, wherein a 5-HT in 30-such as the claim 27 to 29 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof,
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof, or
6-methoxyl group-8-[4-(1-quinoline-8-base-piperidin-4-yl)-piperazine-1-yl]-quinoline and pharmaceutically useful acid-addition salts thereof.
31. as any described pharmaceutical composition, wherein a 5-HT in the claim 27 to 30 1AAgonist compounds is
(R)-4-cyano group-N-{2-[4-(2,3-dihydro-benzo [1,4] dioxine-5-yl)-piperazine-1-yl] propyl group }-N-pyridine-2-base-Benzoylamide and pharmaceutically useful acid-addition salts thereof, or
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof.
32. as any described pharmaceutical composition, wherein a 5-HT in the claim 27 to 31 1AAgonist compounds is
(R)-N-(2-methyl-(4-indyl-1-piperazinyl) ethyl)-N-(2-pyridine radicals) cyclohexane carboxamide and pharmaceutically useful acid-addition salts thereof.
33. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is a cholinesterase inhibitor.
34. pharmaceutical composition as claimed in claim 33, wherein cholinesterase inhibitor is tacrine, donepezil, sharp this bright or galantamine.
35. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is nmda antagonist or NMDA agonist.
36. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the ampakine compounds.
37. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is a BZD/GABA receptor complex regulator.
38. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is a 5-hydroxytryptamine antagonist.
39. as any described pharmaceutical composition in the claim 22 to 27, wherein cognitive enhancer is the nicotine type nicotinic chemical compound.
40. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the muscarinic type chemical compound.
41. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the MAO-B inhibitor.
42. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the PDE inhibitor.
43. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the G protein compound.
44. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is a channel modulators.
45. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the immunization therapy compounds.
46. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is the anti-amyloid medicine or falls the amyloid medicine.
47. as any described pharmaceutical composition in the claim 27 to 32, wherein cognitive enhancer is Statins or PPARS regulator.
48. as any described pharmaceutical composition in the claim 27 to 47, wherein this pharmaceutical composition comprises the preparation that is suitable for oral delivery.
49. as any described pharmaceutical composition in the claim 27 to 48, wherein this pharmaceutical composition comprises the preparation that is suitable for slow release.
50., wherein have the 5-HT of cooperative effective quantity as any described pharmaceutical composition in the claim 27 to 49 1AAgonist compounds and cognitive enhancer.
51. comprise 5-HT 1AThe packing of antagonist and cognitive enhancer, wherein description comprises the explanation that is used for the treatment of cognitive disorder.
52. comprise 5-HT 1AAntagonist and cognitive enhancer be as the medicine of combination preparation, and it is used for simultaneously, respectively or successively make and be used for treating cognitive disorder.
53.5-HT 1AAntagonist and the cognitive enhancer purposes in the medicine of preparation treatment cognitive disorder.
54. cognitive enhancer is at preparation and 5-HT 1APurposes in the medicine of the treatment cognitive disorder of antagonist coupling.
55.5-HT 1AThe purposes of antagonist in the medicine of the treatment cognitive disorder of preparation and cognitive enhancer coupling.
CNA2007800205620A 2006-06-09 2007-06-07 Method for enhancing cognitive function Pending CN101466365A (en)

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